Project Summary: This proposal studies how activation of a key cytoplasmic innate immune receptor, the pattern recognition receptor AIM2, regulates activation of the NLRP3 inflammasome and thus protects from renal tubular epithelial cell (RTE) injury. The project is highly significant for acute kidney injury, which occurs frequently and leads to the burden of chronic kidney disease. Broad/long-term objectives: The long-term goals of the proposed research are to define how activation of AIM2 regulates injury responses in the kidney in the setting of ischemia reperfusion injury. Aim 1 asks how AIM2 regulates the NLRP3 inflammasome (a well-described trigger of renal IR injury) in RTE cells (the cell type most vulnerable to renal IR injury), by defining the mechanisms by which AIM2 regulates NLRP3 inflammasome priming, assembly; and subsequent release of IL1b/IL18 and pyroptosis. Aim 2 focuses on understanding the relative role of AIM2 in the kidney in vivo. The experiments in this aim will broadly assess kidney-specific mediators of injury vs. inflammatory mediators of injury using a kidney transplant model that allows injury responses of the aim2-/- kidney to be studied in a WT host, and WT kidney injury to be studied in the aim2-/- host. Health Relatedness of Project: If the aims of this proposal are met we will learn how AIM2 participates as a negative regulator of injury responses in the kidney. This knowledge is crucial for the development of rational targeted therapies for prevention or amelioration of renal injury in clinical situations where hypoxia is anticipated. Focusing on the earliest events of ischemic kidney injury holds the greatest promise for effective therapeutic strategies.